Function and size of the residual kidney after treatment of Wilms tumor.

Long-term damage to the residual kidney is of concern in the survivors of Wilms tumor. Our objective was to evaluate the long-term glomerular function and size of the residual kidney in these patients. Twenty-nine survivors of Wilms tumor diagnosed between July 1999 and June 2004 were enrolled. The glomerular function was assessed by creatinine clearance, 99mTc DTPA radionuclide scintigraphy and 24-hour urinary protein. Renal size was evaluated by ultrasonography. Median age at diagnosis and at enrollment were 2.87 ± 1.8 (range: 0.5-7.5) and 7.9 ± 3.8 years (range: 2.5-18). Median duration of follow-up was 4.78 ± 2.6 years (range: 1-8.8). Evidence of renal dysfunction in the form of either function or size was identified in eight (27.6%) children. Six children had subnormal glomerular filtration rate and one had proteinuria. Subnormal size of the residual kidney was observed in one child. Age at diagnosis, stage, and duration elapsed after nephrectomy had no association with renal dysfunction (P >.05). Long-term follow up is crucial to identify clinical nephrotoxicity among survivors of Wilms tumor.

Spectrum of diseases diagnosed on bone marrow examination of 285 infants in a single tertiary care center.

OBJECTIVES: Bone marrow (BM) aspiration and trephine biopsy is one of the most valuable procedures in the evaluation of hematological disorders. There is a shortage of published literature regarding the indications, procedure, and outcome of bone marrow examination (BME) in neonates and infants. The aim of the present study is to analyze the common indications of performing BME and to assess the spectrum of disorders diagnosed from BM of neonates and infants. METHODS: A retrospective analysis of BMEs performed in infants over a period of 5 years, between 2009 and 2013 was done. RESULTS AND DISCUSSION: A total of 297 BME were performed on 285 infants, which constitutes 10.3% of pediatric BME procedures during the same period. In our institute, BME is routinely performed by trained pathologists from posterior superior iliac spine in children including infants and neonates with an overall sample adequacy of 97%. Evaluation of cytopenias and suspicion of storage disorder were the most common indications for BME procedure, while acute leukemias and storage disorders were the most common diagnoses offered in infant BM. CONCLUSIONS: Posterior superior iliac spine is a good site of BME in neonates and infants. BM trephine biopsy is a difficult procedure in this age group, however remains indispensable in situations where an infiltrative pathology is suspected. BME not only helps to make specific diagnoses but should also be used as an extremely valuable, quick, and economically viable procedure to exclude major hematological disorders including certain forms of storage disorder and hematological malignancy in this age group.

Bone Marrow Involvement in Neuroblastoma: A Study of Hemato-morphological Features.

Bone marrow involvement in neuroblastoma indicates advanced stage of disease. The recent use of autologous bone marrow "rescue", has provided an additional important reason for accurate assessment of bone marrow status in newly diagnosed patients. In this study, we analyzed 44 cases of neuroblastoma for bone marrow infiltration status and their hematological parameters. Eighty-eight bone marrow aspirate and trephine touch imprint smears and 44 trephine biopsy sections were examined in these 44 patients. Of these, 24 cases (54.5 %) showed marrow infiltration. Leucopenia and bicytopenia were significantly (p < 0.05) associated with marrow infiltration. Both bone marrow aspirate and biopsy were positive for infiltration in 16 out of 24 positive cases. Only aspirate smears were positive in 4 and only trephine biopsy in another 4 cases. The pattern of infiltration consisted of rosette formation in 40.7 % cases on aspirate smears and 22.2 % cases in trephine biopsies. Remaining cases showed diffuse and interstitial presence of tumor cells and cases positive only on trephine biopsy, showed marked stromal reaction. Bilateral trephine biopsies combined with aspirate smears picked up all positive cases compared to when they were assessed alone.

Medication errors on oral chemotherapy in children with acute lymphoblastic leukemia in a developing country.

BACKGROUND: Medication errors occur universally. Inappropriate administration of chemotherapy drugs can have adverse effects in cancer patients. Our objective was to assess the rate and type of medication errors in children with acute lymphoblastic leukemia (ALL) receiving oral chemotherapy in outpatient setting. PROCEDURE: Prescription and administration of oral chemotherapy drugs in children with ALL were evaluated prospectively to determine rate and type of medication errors. Errors were defined as prescription (physician) level or administration (patient) level errors. RESULTS: Two hundred eighty-nine drugs were prescribed to 121 patients. Medication errors occurred in 36 (12.5%) prescriptions; 21(7.3%) were administration errors, 13 (4.5%) were prescribing errors, and two errors occurred at both levels. Mercaptopurine (6-MP) was significantly associated with higher rates of errors (Odds ratio [OR] = 2.1, 95% CI [confidence interval] 1-4.1) whereas lapses were less with dexamethasone (OR = 0.25, 95% CI 0.09-0.67). As a result of medication errors 28 (23.1%) patients received inappropriate doses. Twenty five (21%) patients received sub-optimal doses whereas three got higher doses of chemotherapy. On univariate analysis, socioeconomic status, education status of the caregiver, 6-MP and methotrexate were significantly associated with errors (P ≤ 0.05). On multivariate analysis, ≤ primary school education of the caregiver and prescription of methotrexate were independent predictors of errors. CONCLUSIONS: Medication errors affected nearly one fourth of the children receiving oral chemotherapy. Future studies are needed to look at effective interventions to avoid chemotherapy associated errors especially amongst the lower strata of society.

Alloimmunization and autoimmunization in transfusion dependent thalassemia major patients: Study on 319 patients.

BACKGROUND: The development of anti-red blood cell antibodies (both allo-and autoantibodies) remains a major problem in thalassemia major patients. We studied the frequency of red blood cell (RBC) alloimmunization and autoimmunization among thalassemia patients who received regular transfusions at our center and analyzed the factors, which may be responsible for development of these antibodies. MATERIALS AND METHODS: The study was carried out on 319 multiply transfused patients with ß-thalassemia major registered with thalassemia clinic at our institute. Clinical and transfusion records of all the patients were examined for age of patients, age at initiation of transfusion therapy, total number of blood units transfused, transfusion interval, status of splenectomy or other interventions. Alloantibody screening and identification was done using three cell and 11 cell panel (Diapanel, Bio-rad, Switzerland) respectively. To detect autoantibodies, autocontrol was carried out using polyspecific coombs (IgG + C3d) gel cards. RESULTS: Eighteen patients out of total 319 patients (5.64%) developed alloantibodies and 90 (28.2%) developed autoantibodies. Nine out of 18 patients with alloantibodies also had autoantibodies. Age at first transfusion was significantly higher in alloimmunized than non-immunized patients (P = 0.042). Out of 23 alloantibodies, 52.17% belonged to Rh blood group system (Anti-E = 17%, Anti D = 13%, Anti-C = 13%, Anti-C(w) = 9%), 35% belonged to Kell blood group system, 9% of Kidd and 4% of Xg blood group system. CONCLUSION: Alloimmunization was detected in 5.64% of multitransfused thalassemia patients. Rh and Kell blood group system antibodies accounted for more than 80% of alloantibodies. This study re-emphasizes the need for RBC antigen typing before first transfusion and issue of antigen matched blood (at least for Rh and Kell antigen). Early institution of transfusion therapy after diagnosis is another means of decreasing alloimmunization.

Unusual sites of relapse in pre-B acute lymphoblastic leukemia.

Relapses of acute lymphoblastic leukemia (ALL) in unusual sites can be challenging to diagnose. We present unusual relapses occurring in children with ALL treated in a single institution over a 22-year period. Of 172 relapses, 9 (5.2%) were at unusual sites (nonmarrow, testes, central nervous system). The most common site of relapse was ocular (66%). The median symptom-to-diagnosis interval was 20 days. Two of 9 children attained second remission. A possibility of relapse should be considered when evaluating unusual symptoms in a child with underlying ALL.

miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias.

BACKGROUND: microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL. METHODS: Elevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21CIP, CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays. RESULTS: We identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3' untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa). CONCLUSIONS: This study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.

(68)Ga-DOTATATE positron emission tomography/computed tomography scan in the detection of bone metastases in pediatric neuroendocrine tumors.

AIM: The aim of this study is to evaluate the role of (68)Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scan for the detection of bone metastases in pediatric neuroendocrine tumors (NETs) and to compare it with CT scan. MATERIALS AND METHODS: A total of 30 patients (18 were males and 12 were females; age range: 1-18 years; mean age 7.6 years) with histologically confirmed NETs referred to our department were retrospectively analyzed. All patients underwent (68)Ga-DOTATATE PET/CT scan at the time of diagnosis for primary staging. Contrast enhanced CT (CECT) performed at the time of PET scan acquisition was used for comparison with PET data. Imaging results were analyzed on a per-patient and on a per-lesion basis. Clinical follow-up of all patients and repeat PET/CT imaging (n = 10) was taken as the reference standard. RESULTS: Out of the 30 patients, 17 had no evidence of bone metastases on any imaging modality or on clinical follow-up while the rest of 13 patients showed evidence of bone metastases (nine showing positivity both on (68)Ga-DOTATATE PET and CT scan while four showing positivity only on (68)Ga-DOTATATE PET). Compared with CT scan, (68)Ga-DOTATATE PET detected bone metastases at a significantly higher rate (P = 0.0039). On a per lesion analysis, out of a total of 225 lesions detected by (68)Ga-DOTATATE PET, only 84 lesions could be detected by CT scan. CONCLUSION: (68)Ga-DOTATATE PET/CT scan is more useful than CECT scan for the early detection of bone metastases in pediatric NETs.

Risk factors for thromboembolism and pulmonary artery hypertension following splenectomy in children with hereditary spherocytosis.

BACKGROUND: The aim was to study risk-factors for vascular thrombosis and incidence of pulmonary artery hypertension (PAH) in splenectomized children with hereditary spherocytosis (HS) at a single center. PROCEDURE: Pre- and post-splenectomy hemoglobin and platelet counts were recorded. Post-splenectomy lipid-profile, fibrinogen, D-dimer, CRP and anti-coagulant-protein levels were compared to established controls. Echo-Doppler was performed for PAH. RESULTS: Twenty-six children with HS had undergone splenectomy; the mean age at surgery was 7.9 ± 3.7 years. Nineteen of the 26 were prospectively investigated at a median duration of 4.5 years (range: 4 months to 19 years) following splenectomy. Thrombocytosis was observed in 19 (73%), whereas no patient had erythrocytosis at the last follow-up visit. Total cholesterol, LDL-C, HDL-C, and triglyceride levels were not deranged (P ≥ 0.3). Mean CRP levels (males: 2.8 ± 0.5; females: 2.1 ± 0.5 mg/L) were significantly higher than described for normal children (P < 0.001). Six (23%) patients had a positive D-dimer assay. Protein S, anti-thrombin-III and fibrinogen were in range. A single patient had a borderline low protein C activity. Lupus anticoagulant and anti-cardiolipin antibody assays were negative. The mean tricuspid regurgitant jet velocity (TRJV) was 1.8 ± 0.55 meter per second (range: 0-2.4). None had a TRJV ≥2.5 meter per second to suggest PAH. CONCLUSIONS: There was no evidence of PAH, dyslipidemia, elevation of fibrinogen or a reduction in anti-coagulant proteins, at a median follow-up duration of 4.5 years following splenectomy in children with HS. However, elevated CRP level (42%), persistent thrombocytosis (73%) and elevated D-dimer levels (23%) were observed. These have been recognized as risk factors for cerebrovascular and coronary heart disease.

Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling.

We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling). We also discuss main differential diagnoses of epiphyseal stippling and a brief literature review.

HbSD-Punjab: clinical and hematological profile of a rare hemoglobinopathy.

PURPOSE: Compound heterozygous HbSD-Punjab is an uncommon hemoglobinopathy encountered in Indians. Limited literature is available about its clinical course. The aim of this study was to describe the clinical and hematological profile of HbSD-Punjab patients from North India. MATERIALS AND METHODS: HbSD-Punjab patients diagnosed in the hematology clinics between year 2000 and 2010 were reviewed retrospectively. The diagnosis was established using high-performance liquid chromatography, molecular analysis, and family screening. Clinical details, laboratory parameters, and therapy details were recorded from case records. RESULTS: Ten patients were identified. Median age at onset of symptoms was 3.5 years (interquartile range [IQR], 1.9 to 7.2). Clinical presentation included: anemia in 3, painful vaso-occlusive crisis in 2, acute chest syndrome in 2, and 3 were diagnosed incidentally. All had moderate to severe anemia (mean hemoglobin [Hb]: 6.8 ± 1.2 g/dL). Eight required red cell transfusions (median: 3 [IQR, 2 to 8]). On high-performance liquid chromatography, median HbF, HbD, and HbS were 12.1% (IQR, 9 to 18.3), 39.7% (IQR, 35 to 42), and 38.5% (IQR, 29 to 43). Five patients received hydroxyurea (HDU), median dose: 20 mg/kg/d (IQR, 18 to 23) with median duration of 7 months (IQR; 6, 45). Increment in Hb and reduction in painful crisis was observed in response to HDU. CONCLUSIONS: HbSD-Punjab has a heterogeneous clinical presentation. Anemia and sickle crises are quite common. HDU may be considered for those presenting with severe phenotype.

Proteus syndrome: Clinical profile of six patients and review of literature.

OBJECTIVE: Proteus syndrome (PS) is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to development of tumors. Very few cases are reported in literature from developing countries. Due to certain overlapping features with other overgrowth syndromes, diagnosis is usually delayed. Our aim was to describe clinical profile of this rare condition in six patients. MATERIALS AND METHODS: Retrospective case sheet review of patients followed in a Pediatric Genetic and Metabolic clinic at a tertiary care institute of North India with a diagnosis of hemihypertrophy/overgrowth syndrome. RESULTS: Six cases presented with asymmetric overgrowth and peculiar features suggestive of PS were included in this study. Age at presentation was 2 months to 10 years; two were males and four were females. Hemihypertrophy was noticed in only one case at birth, and focal overgrowths in rest of other patients were seen later during childhood. CONCLUSION: Due to certain overlapping features with other overgrowth syndromes, diagnosis of PS is usually delayed. Pediatricians are the first persons who come across such patients and they should be aware about this rare condition.

Acute lymphoblastic leukemia with pancytopenia at presentation: clinical correlates, prognostic impact, and association with survival.

Acute lymphoblastic leukemia has a wide variety of presentations. There is paucity of any data addressing pancytopenia at presentation in acute lymphoblastic leukemia. In this study we assessed 84 patients with pancytopenia at presentation. They had a significantly lower incidence of bulky disease at presentation. A significantly higher fraction of these patients (n=66, 78.57%) opted for therapy (P=0.005) as compared with the rest. The estimated mean survival in patients presenting with pancytopenia (67.2±17.2 mo) was significantly higher (P=0.031, log-rank test) as compared with that of other patients (47.2±7.4 mo). Pancytopenia was an independent predictor of better survival (P=0.043) in multivariate analysis.

Lissencephaly presenting with congenital hypothyroidism.

Lissencephaly is a rare brain malformation characterized by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration. Association of congenital hypothyroidism with lissencephaly is seldom reported. We report a case of lissencephaly with congenital hypothyroidism.

Overlapping phenotypes in OFD type II and OFD type VI: report of two cases.

Mohr syndrome [orofaciodigital (OFD) syndrome type II] is an autosomal recessive condition that presents with short stature, broad or a bifid nasal tip, orofacial clefts, hypertrophied oral frenulae, tongue nodules or lobulated tongue, and digital anomalies. The features of OFD type II overlap with those of OFD type VI, Joubert syndrome, and short rib polydactyly (Majewski syndrome). Patients with OFD seen in our genetics in the last 4 years were reviewed. Of the five patients with OFD seen, two had Y-shaped metacarpals and other abnormalities consistent with the phenotypic spectrum of Mohr syndrome. They also had the additional radiological features of hypoplastic middle phalanges of index fingers and a hypertrophied or enlarged metatarsal with multiple phalanges arising from it. We hypothesize that type II and type VI OFD syndromes represent a continuum of the same phenotypic spectrum with severe central nervous system abnormalities at the more severe end of the spectrum.

Significant male preponderance in childhood acute lymphoblastic leukemia in India and regional variation: tertiary care center experience, systematic review, and evaluation of population-based data.

Although, a slight male preponderance has been reported in childhood acute lymphoblastic leukemia (ALL) from several developed nations, several Indian studies suggest a skewed gender ratio in ALL. To assess the gender ratio at presentation in ALL in India, we used a three-prong approach: (i) center audit, (ii) systematic review of published studies on ALL in India, and (iii) assessment of population based registry data. Data on gender at presentation in ALL were extracted from these multiple sources. In our center audit, we observed a significantly higher of male:female (M:F) ratio of 3.16:1 (P = .046) in ALL as compared to world literature. In the systematic review of all ALL studies from India, 367 articles were identified and reviewed. A total of 4230 and 1843 boys and girls in these studies were assessed and the M:F ratio was 2.503:1; much higher than the world ratio but not significantly different (P = .10). Population-based data obtained from the National Cancer Registry Program also depicted a male preponderance, especially from large cities in India in a consistent manner since 1984. There is also significant (P = .025) interregional variation in the gender ratio in India. Our study clearly demonstrates a consistent male preponderance in childhood ALL in India along with significant interregional variations over the last three decades. There is a clear need of prospective nationwide multicenter assessment of high-resolution data to confirm this important observation and assess its implications, especially on the health care system.

Serum galactomannan assay for the diagnosis of invasive aspergillosis in children with haematological malignancies.

Diagnostic efficacy of Galactomannan (GM) assay for invasive aspergillosis (IA) is variably reported. Data from developing countries are scant. Children with haematological malignancies and fever were enrolled prospectively. Blood sample for GM was drawn on the day of admission; levels were measured with Platellia Aspergillus enzyme immunoassay. Diagnostic criteria were adapted from EORTC-MSG-2002. Proven, probable and possible episodes were considered as the disease group. One hundred febrile episodes in 78 patients were evaluated. The mean age was 6.1 years. Majority (75%) episodes were in patients with acute lymphoblastic leukaemia. One episode each was diagnosed with proven and probable IA, while 23 were diagnosed with possible IA. Best results were obtained with a cut-off value of 1.0, with sensitivity, specificity, positive and negative predictive value of 60%, 93%, 75 and 87 respectively. The sensitivity dropped to 40%, at cut-off value of 1.5 and specificity was 38%, at a cut-off of 0.5. A higher value of GM correlated with pulmonary nodules (P = 0.037) and mortality (P = 0.001). GM assay is adjunctive to clinical/radiological evidence. A negative GM assay may not reassure the physician against the use of amphotericin in patients with febrile neutropenia, as it does not exclude the diagnosis of clinically relevant other fungal infections, particular mucormycosis.

Outcome of neuroblastoma in India.

OBJECTIVES: To assess the outcome of childhood neuroblastoma in India over the last 2 decades, identify management lacunae and suggest remedial measures. METHODS: A comprehensive search to identify literature addressing outcome of childhood neuroblastoma from India was performed. International Society of Paediatric Oncology and American Society of Clinical Oncology Annual-Meeting abstracts were hand searched to identify unpublished data. Clinico-demographic and outcome data was extracted. RESULTS: Outcome of approximately 700 patients has been published over the last 2 decades with predominantly small to moderate single center series from 6 cities. Primarily non-myeloablative multiagent chemotherapy protocols alongwith surgery, have been used for treatment. A large majority of patients had stage III/IV neuroblastoma. Limited diagnostic facilities were available at most centers. Survival outcome of 8.7 to 80 % has been reported with high death and relapse rates alongwith high incomplete control/disease progression and treatment abandonment. Few series have identified prognostic parameters. Few patients with high-risk disease have been adequately treated and cured. CONCLUSIONS: There is a clear need for replicating neuroblastoma outcomes at centers of excellence in other cancer centers, improving diagnostic and laboratory facilities, administering adequate and appropriate contemporary therapy, assessing disease response and improving supportive care. National data management infrastructure along with better financial and social support initiatives are key factors.